Clinical Phenotype and Disease Course of Inflammatory Bowel Disease in Iran: Results of the Iranian Registry of Crohn’s and Colitis (IRCC)

Background: Data on the epidemiology of inflammatory bowel disease (IBD) in the Middle East are scarce. We aimed to describe the clinical phenotype, disease course, and medication usage of IBD cases from Iran in the Middle East. Methods: We conducted a cross-sectional study of registered IBD patients in the Iranian Registry of Crohn’s and Colitis (IRCC) from 2017 until 2022. We collected information on demographic characteristics, past medical history, family history, disease extent and location, extra-intestinal manifestations, IBD medications, and activity using the IBD-control-8 questionnaire and the Manitoba IBD index, admissions history, history of colon cancer, and IBD-related surgeries. Results: In total, 9746 patients with ulcerative colitis (UC) (n=7793), and Crohn’s disease (CD) (n=1953) were reported. The UC to CD ratio was 3.99. The median age at diagnosis was 29.2 (IQR: 22.6,37.6) and 27.6 (IQR: 20.6,37.6) for patients with UC and CD, respectively. The male-to-female ratio was 1.28 in CD patients. A positive family history was observed in 17.9% of UC patients. The majority of UC patients had pancolitis (47%). Ileocolonic involvement was the most common type of involvement in CD patients (43.7%), and the prevalence of stricturing behavior was 4.6%. A prevalence of 0.3% was observed for colorectal cancer among patients with UC. Moreover,15.2% of UC patients and 38.4% of CD patients had been treated with anti-tumor necrosis factor (anti-TNF). Conclusion: In this national registry-based study, there are significant differences in some clinical phenotypes such as the prevalence of extra-intestinal manifestations and treatment strategies such as biological use in different geographical locations.


Introduction
Inflammatory bowel disease (IBD) is a chronic, relapsing inflammation of the gastrointestinal tract and comprises ulcerative colitis (UC) and Crohn's disease (CD).The etiology of the disease is not fully known, but multiple genetic and environmental factors influence the pathogenesis and course of the disease.GI), CD behavior (including inflammatory, fistulizing, stricture forming), history of colon cancer, IBD related surgeries, and extra-intestinal manifestations (including sclerosing cholangitis [PSC], ankylosing spondylitis [AS], autoimmune hepatitis [AIH], erythema nodosum, uveitis, pyoderma gangrenosum [PG], and peripheral arthritis). 21ther general information was obtained through a telephone interview with a research assistant (registrar).The gathered information comprised demographic data, comorbidities, educational background, family history of IBD (including the degree of the affected relative and number of family members with IBD), the disease activity during the past two weeks using the IBD-control-8 questionnaire (with a score above 13 defined as inactive disease), 24 disease activity during the past six months using the Manitoba IBD Index (with a score above four defined as inactive disease), 25 IBD medications (consisting of prednisolone, 5-aminosalicylic acid [5-ASA], immunomodulators, antitumor necrosis factors [anti-TNF]), emergency room visits in the past 12 months, and admissions in the past three months. 21,26ase enrolment was based on the diagnoses of gastroenterologists who worked with the IRCC, and were committed to using standard illness definitions and protocols.The quality of data collection was checked by registrars randomly recording and reviewing interviews.Additionally, our software's architecture includes validation rules that prevent incorrect data from being registered, as well as a monitoring dashboard that allows the executive management to track response times and missing data.Every registrar received training at the IRCC office.To assess the construct validity of clinicianreported questions, there was also a process for randomly testing physician-answered questions.
Statistical analysis was performed using Stata 11.

Results
A total of 9746 patients with confirmed IBD diagnosis were registered in IRCC at the time of writing this paper.Of those, 7793 patients had UC and 1953 patients had CD.The UC to CD ratio in our study cohort was 3.99.

UC Clinical Characteristics
Table 1 shows the clinical characteristics and demographic data of UC patients.The male to female ratio was 1.1 in UC patients.The median age at diagnosis was 29.2 (IQR: 22.6,37.6).The mean duration of the disease was 7.4 years.A first-or second-degree family member with IBD was reported by 17.9% of patients, with 10.6% having a firstdegree relative with IBD.Persian (59.7%) and Azeri (17%) were the most common ethnicities, followed by Kurd (8.8%), Lur (3%), and others (11.4%), such as Arab and Turkmen.

CD Clinical Characteristics
Table 1 shows the clinical characteristics and demographic data of CD patients.The male-to-female ratio was 1.

Discussion
In this study, the prevalence of UC was higher than CD, which is in line with the previous report from 2012, 27 and is similar to the rest of Asia and Western countries. 28This study is the first report on the natural history of IBD, including behavior, clinical outcome, and medication usage from Iran as a representative population of the Middle East, which is among the two most populous countries in this region.
In this study, we observed one peak at 30-40 years, which is similar to previous reports from other countries in Asia. 16However, two age peaks have been reported in patients in Western countries (CD: 20 to 30 and 60-70; UC: 30 to 40 and 60 to 70). 15 This finding could be related to the colorectal cancer screening colonoscopies that are more commonly conducted in Western countries.The lower screening rate in our country may contribute to the underdiagnosis of asymptomatic IBD in older adults.
In this study, we observed male dominancy in CD patients with a male-to-female ratio of 1.28.Gender distributions differ across geographic regions of the world and by age. 29hile data from North America, [30][31][32] Scandinavia 33 and Europe 34 show greater female incidence compared to males, the reverse has been reported from Eastern countries with male to female ratios ranging from 1.5 to 3.3. 28These geographical differences raise speculation that there may be genetic and environmental factors playing a role in the pathogenesis that need further investigation.

Inflammatory bowel disease in Iran
In this study, most UC cases had pancolitis followed by left colitis and proctitis.Among Southeast Asian patients, pancolitis has been the most common UC extent (39.5%; range, 28%-56%), followed by left-sided colitis (37%; range, 22%-58%). 28In a meta-analysis, pancolitis was the predominant location of disease in the USA (57.69-60.72%),and proctitis was the least common (8.82 and 8.53%). 35Reports from the Middle East show extensive colitis predominance (42.7%-45.5%) in Lebanon and Saudi Arabia. 36,37However, in Qatar and the UAE, leftside colitis was the most common UC extent (48%-55%). 6imilarly, left-sided colitis was dominant (50%) in a report from Western Hungary 38 and Brazil. 39And, data from Scandinavia show an even distribution of UC extent. 40n summary, the extension of UC patients is comparable between Asian countries and the West.
Regarding disease location in CD patients, in this study, ileocolonic was the most common type (43.7%), followed by ileal and colonic.The Western literature demonstrates relatively equal proportions of CD patients with ileal, colonic, or ileocolonic involvement.In a metaanalysis from the USA, the distribution of CD location was 42% ileocolonic, 28% ileal, and 28% colonic. 35A European Collaborative Study Group on Inflammatory Bowel reported 47.4% colonic, 33.9% ileocolonic, and 18.6% ileal. 41Data from Scandinavia shows 49% colonic involvement followed by 28% ileal and 23% ileocolonic. 408][19][20] In summary, the clinical presentations of CD patients are comparable between Asian countries and the West.
Among Asian patients, fistulizing behavior ranges 7-18%, and stricturing behavior has been reported between 8-32%. 28A meta-analysis calculated 27.7% fistulizing and 16.8% stricturing behavior in the USA, 35 And data from Scandinavia show 10% fistulizing and 13% stricturing behavior. 40In this study, the prevalence of stricturing behavior was only 4.6%, which is lower than other reports, while the prevalence of fistulizing behavior (11%) was similar to Asian countries and lower than the West.In this regard, one contributing factor may be that 3D imaging is not commonly used in Iran, and access to MR enterography, CT enterography, and transrectal EUS is limited.Therefore, underdiagnosis may lead to a lower prevalence of fistulizing and stricturing behavior observed in this study.
Reported frequencies of extra-intestinal manifestations in IBD range from 6% to 47%, with a frequency of 10-25% in Western countries. 42Observed frequency of 5.2% in patients with UC and 3.6% among patients with CD highlights the importance of comprehensive examination of patients and the need to include this topic in the continuing medical education (CME) programs.In addition, this study gathered data from the gastroenterologists, and due to the lack of universal electronic health care records, it could be possible that these patients had records of extra-intestinal manifestation in their charts with other specialties (rheumatologist, dermatologists, ophthalmologists, etc) that were missed.
Globally, the colectomy rate and colorectal cancer in IBD patients has decreased over the past decade, 43,44 and the use of biological medications has led to lower need for surgery.Previously, a matched cohort study in America revealed a higher incidence of rectal tumors among UC but not CD patients, 45 and a large study from England reported the prevalence of colorectal cancer to be 1.3% among patients with IBD. 46Our study showed a prevalence of 0.3% for colorectal cancer among patients with UC.It is important to interpret these estimates for surveillance strategies.Of note, higher reported rates in Western countries could also be attributed to better documentation, and future studies should investigate the IBD registry and the cancer registry database together to account for IBD patients who presented with colorectal cancer and underwent colectomy.However, the difference in genetic and environmental factors may also play a role that needs further investigation.
The usage of anti-TNF and biological agents in this study was lower compared to Western countries, which could be attributed to the limited insurance coverage and lack of access to other types of biologics and small molecules (Infliximab, Adalimumab and Tofacitinib are the only available medications in Iran).Our team, as the focal point of physicians' and patients' education on IBD, has been organizing workshops in each province of Iran to increase the knowledge of physicians and patients about the treatment modalities and biologic drugs to start treatment in early stages and prevent morbidity due to cancer, colectomy, stricture or fistula.Adalimumab was used more than infliximab among both UC and CD patients, which could be due to the easier process of commencing (subcutaneous vs. intravenous), considering the more limited access to intravenous injections in rural areas.The high prevalence of 5-ASA usage among CD patients in our cohort is a sign of malpractice, and since CD is a transmural disease and 5-ASA does not have an established role in CD treatments, there is a need for a change of practice.In this regard, there are active plans for incorporating this topic in CMEs.The limited use of methotrexate in this cohort, as well as its roles in decreasing antibodies against biological medications, disease control, and lower cost, highlight the need for the education of physicians to leverage this option in the treatment of patients.
The referral nature of our centers in this study can lead to selection bias; however, we have included the majority of gastroenterologists in all the provinces of Iran.Moreover, the participation rate was different by provinces in the IRCC.While part of the data extraction was based on clinical records, the research assistant asked retrospective questions from the patient, which might have contributed to recall bias.Moreover, reported medication use in our study was determined by the history of any IBD-related medication intake.Furthermore, this study did not investigate the length and dose of medications.

Conclusion
In this national registry-based study, there are significant differences in some clinical phenotypes such as the prevalence of extra-intestinal manifestations and treatment strategies such as biological use in different geographical locations.More inclusive epidemiological studies are needed to characterize patients with IBD from underrepresented populations to reduce the disease burden worldwide.

Table 1 .
Clinical Characteristics and Demographic Features of IBD Patients

Variables a,b IBD UC (N = 7793) CD (N = 1953)
IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn's disease.a Percentages do not include missing values and were calculated for each row by dividing on the corresponding N value.b Percentages from each subcategory may not add up to the exact number of total reported cases due to missing values and/or non-mutually exclusive variables.

Table 2 .
Clinical Phenotype, Disease Course and Outcomes of IBD Patients a Percentages do not include missing values and were calculated for each row by dividing on the corresponding N value.b Percentages from each subcategory may not add up to the exact number of total reported cases due to missing values and/or non-mutually exclusive variables.